Orally dispersible tablet

ABSTRACT

The present invention provides a preparation with improved disintegration property, a preparation showing improved bioavailability of a medicament, production methods thereof and the like. A rapidly disintegrating preparation comprising granules comprising a medicament coated with a coating layer containing sugar or sugar alcohol; and a disintegrant. A production method of a rapidly disintegrating preparation including a step of producing granules comprising a medicament, a step of forming a coating layer containing sugar or sugar alcohol on the obtained granules and a step of mixing the coated granules with a disintegrant and molding the mixture.

TECHNICAL FIELD

The present invention relates to a preparation with improveddisintegration property, a preparation with improved bioavailability ofmedicament, production methods thereof and the like.

BACKGROUND OF THE INVENTION

Patent document 1 discloses a tablet containing sugar alcohol orsaccharide having an average particle size of 30 μm or below, an activeingredient and a disintegrant, and a production method of a tabletcomprising compression molding a mixture containing sugar alcohol orsugar having an average particle size of 30 μm or below, an activeingredient and a disintegrant.

Patent document 2 discloses an orally dispersible solid pharmaceuticalcomposition of agomelatine, which contains agomelatine and granules ofsimultaneously-dried lactose and starch.

Patent document 3 discloses an orally dispersible, coated solidpharmaceutical composition of agomelatine, which contains a central coreor a central layer comprising agomelatine and excipients allowing anorally dispersible formulation to be obtained, and an orally dispersiblecoating.

However, patent documents 1-3 do not disclose improvement of preparationcharacteristics such as disintegration property and the like byenclosing components such as masking agent, binder and the like thatprevent disintegration in granules.

DOCUMENT LIST Patent Documents

-   patent document 1: WO1997/047287-   patent document 2: JP-A-2005-523253-   patent document 3: JP-A-2007-182440

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a novel formulationtechnique capable of improving disintegration property. In addition,another object of the present invention is to provide a preparationuseful as an orally rapidly disintegrating preparation. Moreover, anobject of the present invention is to provide a preparation capable ofpromoting medicament absorption from the oral mucosa by rapiddisintegration after sublingual administration, and improving themedicament bioavailability.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt tosolve the aforementioned problems and found that the disintegrationproperty of a medicament can be improved and the bioavailability thereofcan also be improved by containing a component that preventsdisintegration (masking agent, binder and the like) as a granulationcomponent in granules, and formulating the preparation after coating asurface of the granule with sugar or sugar alcohol, which resulted inthe completion of the present invention.

Accordingly, the present invention provides the following.

-   [1] A rapidly disintegrating preparation comprising granules    comprising a medicament coated with a coating layer containing sugar    or sugar alcohol; and a disintegrant (hereinafter sometimes to be    abbreviated as preparation [1], the same for the following [2] to    [18]).-   [2] The rapidly disintegrating preparation of the above-mentioned    [1], wherein the granules comprising a medicament further contains a    binder.-   [3] The rapidly disintegrating preparation of the above-mentioned    [1], wherein the granules comprising a medicament further contains a    masking agent.-   [4] The rapidly disintegrating preparation of the above-mentioned    [1], wherein the granules comprising a medicament further contains a    solubilizer.-   [4-1] The rapidly disintegrating preparation of any of the    above-mentioned [1]-[4], wherein the disintegration time is not more    than 30 sec.-   [4-2] The rapidly disintegrating preparation of any of the    above-mentioned [1]-[4], wherein the disintegration time is not more    than 30 sec and the absolute hardness is not less than 1.0 N/mm².

The “rapidly disintegrating preparation” of the present invention isalso superior as a preparation for allowing absorption of a medicamentfrom the oral mucosa. Specifically, it is as described below.

-   [5] The preparation of any of the above-mentioned [1]-[4], which is    for oral-mucosal absorption.-   [6] The preparation of the above-mentioned [5], wherein the    medicament is    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    (general name ramelteon; hereinafter sometimes to be abbreviated as    compound A).-   [7] The preparation of the above-mentioned [5] or [6], which is a    tablet.-   [8] A method of producing a rapidly disintegrating preparation,    comprising a step of producing granules comprising a medicament,-   a step of forming a coating layer containing sugar or sugar alcohol    on the obtained granules, and-   a step of mixing the coated granules with a disintegrant and molding    the mixture.

In addition to the above-mentioned preparation [6], the presentinventors have conducted intensive studies of a preparation superior inthe absorption of compound A from the oral mucosa, and showing improvedbioavailability thereof, and complete the following invention.

-   [9] A preparation for oral-mucosal absorption comprising    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    as a medicament; which shows a higher ratio of the medicament in an    unchanged form and a metabolite of the medicament (i.e., medicament    in unchanged form/metabolite of the medicament) after transfer into    blood than that by oral administration.-   [10] A preparation for oral-mucosal absorption comprising    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    as a medicament; which shows a higher ratio of the medicament in an    unchanged form and a metabolite of the medicament after transfer    into blood than that by oral administration, and a disintegration    time of not more than 30 sec.-   [11] A preparation for oral-mucosal absorption comprising    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    as a medicament; which shows a higher ratio of the medicament in an    unchanged form and a metabolite of the medicament after transfer    into blood than that by oral administration, a disintegration time    of not more than 30 sec, and absolute hardness of not less than 1.0    N/mm².-   [12] A preparation for oral-mucosal absorption comprising    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    and a masking agent; which shows not less than about 10-fold    improved bioavailability of    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,    as compared to that by oral administration.-   [13] A preparation for oral-mucosal absorption comprising    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    and a masking agent; which shows not less than about 10-fold    improved bioavailability of    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,    as compared to that by oral administration, and a disintegration    time of not more than 30 sec.-   [14] A preparation for oral-mucosal absorption comprising    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    and a masking agent; which shows not less than about 10-fold    improved bioavailability of    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,    as compared to that by oral administration, a disintegration time of    not more than 30 sec, and absolute hardness of not less than 1.0    N/mm².-   [15] A preparation for oral-mucosal absorption comprising    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,    sugar or sugar alcohol, and a disintegrant; which shows not less    than about 10-fold improved bioavailability of    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,    as compared to that by oral administration, and a disintegration    time of not more than 30 sec.-   [16] A preparation for oral-mucosal absorption comprising    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,    sugar or sugar alcohol, and a disintegrant; which shows not less    than about 10-fold improved bioavailability of    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,    as compared to that by oral administration, a disintegration time of    not more than 30 sec, and absolute hardness of not less than 1.0    N/mm².-   [17] The preparation of any of the above-mentioned [9]-[16], which    is a tablet.-   [18] The preparation of the above-mentioned [9] or [12], which is in    the form of a film, troche, solution, suspension, freeze-dried    preparation, chewing gum or spray.-   [19] A method for the prophylaxis and/or treatment of a bipolar    disorder comprising administering    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    oral-mucosally to a human.-   [20] The method of the above-mentioned [19], wherein the    oral-mucosal administration is sublingual administration or buccal    administration (more preferably sublingual administration).-   [21] The method of the above-mentioned [19], wherein    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    is administered in 0.05-1.0 mg per day.-   [22] The method of the above-mentioned [19], wherein the bipolar    disorder is bipolar disorder I.-   [23] The method of the above-mentioned [19], wherein the prophylaxis    and/or treatment of a bipolar disorder is a treatment of a    depression symptom associated with the bipolar disorder or    maintenance of a remission phase of the bipolar disorder.-   [24] A drug for the prophylaxis and/or treatment of a bipolar    disorder, which comprises, as an active ingredient,    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    to be oral-mucosally administered to a human.-   [25] The drug of the above-mentioned [24], wherein the oral-mucosal    administration is sublingual administration or buccal administration    (more preferably sublingual administration).-   [26] The drug of the above-mentioned [24], wherein    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    is administered in 0.05-1.0 mg per day.-   [27] The drug of the above-mentioned [24], wherein the bipolar    disorder is bipolar disorder I.-   [28] The method of the above-mentioned [24], wherein the prophylaxis    and/or treatment of a bipolar disorder is a treatment of a    depression symptom associated with the bipolar disorder or    maintenance of a remission phase of the bipolar disorder.-   [29]    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    for the prophylaxis and/or treatment of a bipolar disorder by    oral-mucosal administration to a human.-   [30] The    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    of the above-mentioned [29], wherein the oral-mucosal administration    is sublingual administration or buccal administration (more    preferably sublingual administration).-   [31] The    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    of the above-mentioned [29], which is administered in 0.05-1.0 mg    per day.-   [32] The    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    of the above-mentioned [29], wherein the bipolar disorder is bipolar    disorder I.-   [33] The    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    of the above-mentioned [29], wherein the prophylaxis and/or    treatment of the bipolar disorder is a treatment of a depression    symptom associated with the bipolar disorder or maintenance of a    remission phase of the bipolar disorder.-   [34] The method of the above-mentioned [19]-[23], wherein    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    is administered as the preparation of the above-mentioned [5]-[7],    or [9]-[18].-   [35] The drug of the above-mentioned [24]-[28], wherein    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    is administered as the preparation of the above-mentioned [5]-[7],    or [9]-[18].-   [36] The    (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide    of the above-mentioned [29]-[33], which is administered as the    preparation of the above-mentioned [5]-[7], or [9]-[18].

Effect of the Invention

According to the present invention, a rapidly disintegrating preparationsuperior in the disintegration property, a preparation with improvedmedicament bioavailability and production methods thereof and the likecan be provided.

The rapidly disintegrating preparations [1] to [7] of the presentinvention contain a medicament in granules, and a disintegrant as anextragranule component. Even when a medicament (e.g., compound A etc.)with poor compatibility with the disintegrant is to be used, therefore,an influence of the disintegrant on the medicament can be reduced, thusimproving the stability of the medicament.

The rapidly disintegrating preparation of the present invention canimprove disintegration property by enclosing a component that preventsdisintegration (e.g., masking agent, binder etc.) in granules. Inaddition, it can achieve high disintegration property by ensuring theinvasion route of water into the preparation by coating the componentthat prevents disintegration with sugar or sugar alcohol. Moreover, inthe rapidly disintegrating preparation of the present invention, amedicament is coated with sugar or sugar alcohol. Therefore, thedissolution property of the medicament from the preparation can beimproved even when the medicament has high surface hydrophobicity, byaltering the surface to be hydrophilic.

The rapidly disintegrating preparation of the present invention canachieve both the good disintegration property and the good preparationhardness.

Among the rapidly disintegrating preparations [1] to [7] of the presentinvention, the rapidly disintegrating

preparations [5] to [7] for oral-mucosal absorption of the presentinvention are expected to provide an immediate effect by absorption ofthe medicament from the oral mucosa.

The rapidly disintegrating preparation for oral-mucosal absorption ofthe present invention can improve bioavailability by increasing theblood concentration of a medicament (e.g., compound A etc.) susceptibleto a first pass effect by oral administration. In addition, the rapidlydisintegrating preparation for oral-mucosal absorption of the presentinvention can suppress inconsistent absorption of such medicaments, andfurther, inconsistent effectiveness as medicaments. Moreover, therapidly disintegrating preparation for oral-mucosal absorption of thepresent invention can afford a low dose medicament and a compactpreparation based on the improved medicament bioavailability.

According to the production method of the present invention, the rapidlydisintegrating preparations [1] to [7] of the present invention havingthe above-mentioned effects can be produced.

DESCRIPTION OF EMBODIMENTS

The rapidly disintegrating preparation of the present invention isexplained in detail in the following.

The rapidly disintegrating preparation of the present invention containsgranules comprising a medicament coated with a coating layer containingsugar or sugar alcohol, and a disintegrant.

While the medicament to be used in the present invention is notparticularly limited, for example, antipyretic analgesic antiphlogisticdrugs, antipsychotic drugs, antianxiety drugs, antidepressant drugs,sedative-hypnotic drugs, gastrointestinal drugs, antacid drugs,antitussive expectorant drugs, antihypertensive agents, drugs fordiabetes, drugs for osteoporosis, skeleton muscle relaxants, anti-canceragents and the like can be recited.

In the rapidly disintegrating preparation of the present invention, thecontent of the medicament is generally 0.03-50 wt %, preferably 0.03-20wt %, more preferably 0.03-3 wt %, relative to the total weight of thepreparation.

The rapidly disintegrating preparation of the present invention containsa disintegrant as an extragranule component, and therefore, an influenceof the disintegrant on the medicament can be reduced even when amedicament having poor compatibility with the disintegrant is used, andthe medicament stability can be improved. Thus, the present invention isparticularly effective when a medicament having poor compatibility withthe disintegrant (e.g. compound A, etc) is used as a medicament.

Compound A is a known therapeutic agent for sleep disorders, which isdisclosed in U.S. Pat. No. 6,034,239 and the like, and can be producedby a known method such as the method described in this document and thelike.

In the rapidly disintegrating preparation of the present invention, anexcipient is contained in granules comprising a medicament coated with acoating layer containing sugar or sugar alcohol.

Examples of the excipient include starches such as corn starch and thelike; sugar or sugar alcohols such as lactose, fructose, glucose,mannitol (e.g., D-mannitol), sorbitol (e.g., D-sorbitol), erythritol(e.g., D-erythritol), sucrose and the like: anhydrous calcium phosphate,microcrystalline cellulose, micromicrocrystalline cellulose, powderedglycyrrhiza, sodium hydrogen carbonate, calcium phosphate, calciumsulfate, calcium carbonate, precipitated calcium carbonate, calciumsilicate and the like, and corn starch, D-mannitol and microcrystallinecellulose are preferable.

The content of the excipient is generally 13-94 wt %, preferably 54-94wt %, more preferably 81-93 wt %, relative to the total weight of thepreparation.

The rapidly disintegrating preparation of the present invention mayfurther contain an additive, where necessary, in the granules comprisinga medicament.

Examples of the additive optionally contained in the granules comprisinga medicament include binder, masking agent, solubilizer and the like,which may be used in combination where necessary.

Examples of the binder include starches such as potato starch, wheatstarch, rice starch, partly pregelatinized starch, pregelatinizedstarch, porous starch and the like, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, starch, gumarabic powder, tragacanth, carmellose, sodium alginate, pullulan,glycerol and the like, and partly pregelatinized starch,hydroxypropylcellulose and pregelatinized starch are preferable.

The content of the binder is generally 0.5-20 wt %, preferably 0.5-15 wt%, more preferably 1-10 wt %, relative to the total weight of thepreparation.

Examples of the masking agent include various flavoring agents(thaumatin, sucralose, saccharin, aspartame, xylitol, citric acid,L-sodium glutamate etc.), various receptor antagonists (BENECOAT, sodiumchloride etc.), various cation channel antagonists (L-arginine etc.),various clathration agents (α-cyclodextrin, β-cyclodextrin etc.),various flavors (strawberry flavor, mint flavor, orange flavor, vanillinetc.) and the like. Two or more thereof may be used in combination wherenecessary.

The content of the masking agent is generally 0.01-10 wt %, preferably0.01-5 wt %, more preferably 0.01-1 wt %, relative to the total weightof the preparation.

Examples of the solubilizer include various aqueous solvents(polyethylene glycol, propylene glycol, glycerol etc.), variousclathration agents (α-cyclodextrin, β-cyclodextrin etc.), varioussurfactants (sodium lauryl sulfate, polysorbate 80,polyoxyethylene(160)polyoxypropylene(30)glycol etc.) and the like. Twoor more thereof may be used in combination where necessary.

The content of the solubilizer is generally not more than 20 wt %,preferably not more than 15 wt %, more preferably not more than 10 wt %,relative to the total weight of the preparation.

In the rapidly disintegrating preparation of the present invention,disintegration property can be improved by including a component thatprevents disintegration (e.g., masking agent, binder, solubilizer etc.)in granules. In addition, as mentioned below, the preparation canachieve high disintegration property by ensuring the invasion route ofwater into the preparation by coating the component that preventsdisintegration with sugar or sugar alcohol.

The rapidly disintegrating preparation of the present invention containssugar or sugar alcohol in a coating layer formed on the granulescomprising a medicament.

Examples of the sugar or sugar alcohol include lactose, fructose,glucose, mannitol (e.g., D-mannitol), sorbitol (e.g., D-sorbitol),erythritol (e.g., D-erythritol); sucrose and the like, and D-mannitol ispreferable.

The preparation can achieve high disintegration property by ensuring theinvasion route of water into the preparation by coating the granulescomprising a medicament with sugar or sugar alcohol. In addition, thedissolution property of the medicament from the preparation can beimproved.

The content of the sugar contained in the coating layer is generally5-20 wt %, preferably 5-15 wt %, more preferably 5-10 wt %, relative tothe total weight of the preparation.

The content of the sugar alcohol contained in the coating layer isgenerally 5-20 wt %, preferably 5-15 wt %, more preferably 5-10 wt %,relative to the total weight of the preparation.

The content of the sugar and sugar alcohol contained in the coatinglayer is generally 5-20 wt %, preferably 5-15 wt %, more preferably 5-10wt %, relative to the total weight of the preparation.

The rapidly disintegrating preparation of the present invention mayfurther contain an additive in the coating layer as necessary.

Examples of the additive optionally contained in the coating layerinclude excipient, disintegrant and the like, which may be used incombination as necessary.

Examples of the excipient include starches such as corn starch and thelike; anhydrous calcium phosphate, microcrystalline cellulose,micromicrocrystalline cellulose, powdered glycyrrhiza, sodium hydrogencarbonate, calcium phosphate, calcium sulfate, calcium carbonate,precipitated calcium carbonate, calcium silicate and the like, and cornstarch and microcrystalline cellulose are preferable.

Examples of the disintegrant include amino acid, starch, corn starch,carmellose, carmellose sodium, carmellose calcium, croscarmellosesodium, crospovidone, low-substituted hydroxypropylcellulose,hydroxypropyl starch, sodium carboxymethyl starch and the like, andcrospovidone and carmellose are preferable.

In the rapidly disintegrating preparation of the present invention, theaverage particle size of the “granules comprising a medicament coatedwith a coating layer containing sugar or sugar alcohol” is generally 50μm-500 μm, preferably 50 μm-355 μm, more preferably 50 μm-150 μm.

In the present specification, the average particle size is a valuemeasured by a laser diffraction particle size analyzer, SYMPATEC:HELOS&RODOS and the like.

In the rapidly disintegrating preparation of the present invention,examples of the disintegrant contained as an extragranule componentinclude amino acid, starch, corn starch, carmellose, carmellose sodium,carmellose calcium, croscarmellose sodium, crospovidone, low-substitutedhydroxypropylcellulose, hydroxypropyl starch, sodium carboxymethylstarch and the like, and crospovidone and carmellose are preferable.

The content of the disintegrant is generally 0.5-15 wt %, preferably1-10 wt %, more preferably 2-5 wt %, relative to the total weight of thepreparation.

In the rapidly disintegrating preparation of the present invention,examples of the lubricant optionally contained as an extragranulecomponent include magnesium stearate, stearic acid, calcium stearate,talc (purified talc), sucrose esters of fatty acid, sodium stearylfumarate and the like, and sodium stearyl fumarate is preferable.

The content of the lubricant is generally 0.5-2 wt %, preferably 0.5-1.5wt %, more preferably 0.5-1 wt %, relative to the total weight of thepreparation.

The rapidly disintegrating preparation of the present invention mayfurther contain an additive as an extragranule component wherenecessary.

Examples of the additive include masking agent, solubilizer and thelike, explained above, which may be used in combination where necessary.

The rapidly disintegrating preparation of the present invention is notonly useful as a so-called “orally disintegratable preparation” aimingat oral administration of a medicament, but also preferable as apreparation for oral-mucosal absorption (particularly, sublingualpreparation, buccal preparation).

The rapidly disintegrating preparation for oral-mucosal absorption ofthe present invention can be expected to show immediate effect byabsorption from the oral mucosa.

The rapidly disintegrating preparation for oral-mucosal absorption ofthe present invention is particularly effective when a medicament (e.g.,compound A etc.) susceptible to a first pass effect by oraladministration is used. The rapidly disintegrating preparation fororal-mucosal absorption of the present invention can improvebioavailability by increasing the blood concentration of suchmedicament. In addition, the rapidly disintegrating preparation fororal-mucosal absorption of the present invention can suppressinconsistent absorption of such medicaments, and further, inconsistenteffectiveness as medicaments. Moreover, the rapidly disintegratingpreparation for oral-mucosal absorption of the present invention canafford a low dose medicament and a compact preparation based on theimproved medicament bioavailability.

When compound A is particularly used as a medicament, the rapidlydisintegrating preparation for oral-mucosal absorption of the presentinvention shows an effect in that the ratio of the medicament in anunchanged form and a metabolite of the medicament after transfer intoblood is higher than that by oral administration. In addition, therapidly disintegrating preparation for oral-mucosal absorption of thepresent invention shows not less than about 10-fold improvedbioavailability of compound A, as compared to that by oraladministration.

While the dosage form of the rapidly disintegrating preparation of thepresent invention is not particularly limited, it is preferably atablet.

When the rapidly disintegrating preparation of the present invention isa tablet, the weight of the preparation is preferably about 20-200 mg.

When the rapidly disintegrating preparation of the present invention isa tablet, the absolute hardness is generally not less than 1.0 N/mm²,preferably not less than 1.5 N/mm², more preferably not less than 2.0N/mm². When the rapidly disintegrating preparation of the presentinvention is a tablet, the absolute hardness is generally not more than5.0 N/mm².

When the rapidly disintegrating preparation of the present invention isa tablet, the disintegration time is generally not more than 30 sec,preferably not more than 15 sec, more preferably not more than 10 sec.When the rapidly disintegrating preparation of the present invention isa tablet, the disintegration time is generally not less than 1 sec.

In the rapidly disintegrating preparation of the present invention, thedisintegration property can be improved by including, in granules, acomponent that prevents disintegration, as described above. In addition,it can achieve high disintegration property by ensuring the invasionroute of water into the preparation by coating the component thatprevents disintegration with sugar or sugar alcohol. Therefore, evenwhen the rapidly disintegrating preparation of the present invention ismolded to have the above-mentioned high absolute hardness, it shows gooddisintegration property. Thus, the rapidly disintegrating preparation ofthe present invention can achieve both the good disintegration propertyand the good preparation hardness.

The rapidly disintegrating preparation of the present inventionpreferably shows a disintegration time of not more than 30 sec, andabsolute hardness of not less than 1.0 N/mm².

The rapidly disintegrating preparation of the present invention can beproduced by a method conventionally used in the pharmaceutical-technicalfield. For example, the preparation can be produced by the followingproduction method of the rapidly disintegrating preparation of thepresent invention.

The production method of the rapidly disintegrating preparation of thepresent invention includes

-   step (1): producing granules comprising a medicament,-   step (2): forming a coating layer containing sugar or sugar alcohol    on the obtained granules, and-   step (3): mixing the coated granules with a disintegrant and molding    the mixture.

In steps (1)-(3), an additive may be further added as necessary. As thekind and amount of the “medicament”, “sugar”, “sugar alcohol”,“disintegrant” and “additive” to be used in steps (1)-(3), thoseexemplified for the above-mentioned rapidly disintegrating preparationcan be mentioned. As the particle size of the coated granules obtainedin step (2), the range exemplified as the particle size of the “granulescomprising a medicament coated with a coating layer containing sugar orsugar alcohol” of the above-mentioned rapidly disintegrating preparationcan be mentioned.

The production of the granule in step (1) and formation of the coatinglayer in step (2) can also be carried out simultaneously.

For example, the preparation can be specifically produced as follows.

Sugar or sugar alcohol (e.g., D-mannitol etc.) is dissolved in asuitable solvent (e.g., water etc.) to give a coating solution.

A medicament (e.g., compound A etc.) and any additive (e.g., excipientsuch as D-mannitol, microcrystalline cellulose and the like, binder suchas partly pregelatinized starch and the like etc.) are mixed to give amixture. The obtained mixture is granulated while spraying the coatingsolution thereon, and dried to give a granulated powder (coatedgranules). The obtained granulated powder (coated granules) may besieved as necessary.

The obtained coated granules, a disintegrant (e.g., crospovidone etc.)and any additive (e.g., lubricant such as sodium stearyl fumarate etc.,and the like) are mixed to give a mixed powder. The obtained mixedpowder is compression-molded to give a tablet.

Here, the mixing (including granulation, drying, sieving and the like)is carried out by using a preparation machine, for example, V-typemixer, tumbler mixer (TM-30, TM-15S; SHOWA KAGAKU KIKAI CO., LTD.:TM20-0-0; Suehiro Kakoki Co., Ltd.), high speed mixer granulator(FM-VG-10; POWREX CORPORATION), universal kneader (HATA IRON WORKS CO.,LTD.), fluid bed dryer granulator (LAB-1, FD-3S, FD-3SN, FD-5S; POWREXCORPORATION), box type vacuum dryer (Kusuki Kikai Seisakusho), powermill grinding machine (P-3, SHOWA KAGAKU KIKAI CO., LTD.),centrifugation rolling granulator (CF-mini, CF-260, CF-360; FreundCorporation), dry type granulator, spray-drying granulator, rollinggranulator (MP-10; POWREX CORPORATION) and the like.

Coating is carried out by using, for example, a preparation machine, forexample, centrifugation rolling granulator (CF-mini, CF-260, CF-360;Freund Corporation), rolling granulator (MP-10; POWREX CORPORATION),general fluidized bed coater, wurster-type coater and the like.

Compression molding is carried out by using, for example, single punchtableting machine (Kikusui Seisakusho Ltd.), rotary tableting machine(AQUARIUS 36K, AQUARIUS 2L; Kikusui Seisakusho Ltd.), AUTOGRAPH(AG-5000B, SHIMADZU Corporation) and the like, and by punching generallyat a pressure of 1-30 kN.

In addition to the application of the above-mentioned “rapidlydisintegrating preparation of the present invention” to compound A, thepresent inventors have intensively studied a preparation superior in theabsorption of compound A from the oral mucosa and having improvedbioavailability of compound A, and completed the following invention.

That is, the present invention also relates to a preparation fororal-mucosal absorption containing compound A as a medicament; whichshows a higher ratio of the medicament in an unchanged form and ametabolite of the medicament after transfer into blood than that by oraladministration (preparations [9] to [11], [17] and [18]) (hereinaftersometimes to be abbreviated as preparation (A) of the presentinvention).

When the dosage form of preparation (A) is a tablet, the disintegrationtime is preferably not more than 30 sec. When the dosage form inpreparation (A) is a tablet, more preferably, the disintegration time isnot more than 30 sec, and the absolute hardness is not less than 1.0N/mm².

The aforementioned preparations [5] to [7] are also encompassed in the“preparation (A)”.

The present invention also relates to a preparation for oral-mucosalabsorption, which contains compound A, and shows not less than about10-fold improved bioavailability of compound A, as compared to that byoral administration (preparations [12] to [18]) (hereinafter sometimesto be abbreviated as preparation (B) of the present invention). Here,“about” means 5% error range. The bioavailability is generally improvedwithin the range of not more than about 30-fold, more specifically notmore than about 20-fold.

When the dosage form of preparation (B) is a tablet, preferably, thedisintegration time is not more than 30 sec. When the dosage form inpreparation (B) is a tablet, more preferably, the disintegration time isnot more than 30 sec, and the absolute hardness is not less than 1.0N/mm².

The aforementioned preparations [5] to [7] are also encompassed in the“preparation (B)”.

Here, whether or not “bioavailability of compound A is improved not lessthan about 10-fold as compared to oral administration” is evaluated asfollows.

Each preparation is administered intravenously, orally ororal-mucosally, the plasma concentration after lapse of each time periodis measured, and the area under the plasma concentration time curve(AUC) is calculated according to the trapezoidal rule. In addition,bioavailability (BA) is calculated according to the following formula.

BA (%)=(oral or oral-mucosal administration AUC/intravenousadministration AUC)×100.

The ratio of the calculated BA by oral-mucosal administration relativeto the calculated BA by oral administration (that is, BA by oral-mucosaladministration/BA by oral administration) is calculated.

In this case, when the “ratio of the BA by oral-mucosal administrationrelative to the BA by oral administration” is not less than 10, thepreparation is evaluated to show “not less than about 10-fold improvedbioavailability of compound A as compared to that by oraladministration”.

As for the specific preparations to be subjected to a test and testmethods, the below-mentioned Experimental Example 3 can be referred to.However, when a substantially similar evaluation is possible, the methodis not limited to that of Experimental Example 3.

The present invention also relates to a preparation for oral-mucosalabsorption, which contains compound A and shows a higher ratio of amedicament in an unchanged form and a metabolite of the medicament aftertransfer into blood than that by oral administration (preparations [9]to [11]) (hereinafter sometimes to be abbreviated as preparation (C) ofthe present invention).

The “greater than the ratio” specifically means not less than about5-fold, preferably not less than about 10-fold. It is generally not morethan about 30-fold, more specifically not more than about 20-fold. Here,“about” means 5% error range.

When the dosage form of preparation (C) is a tablet, preferably, thedisintegration time is not more than 30 sec. When the dosage form ofpreparation (C) is a tablet, more preferably, disintegration time is notmore than 30 sec, and the absolute hardness is not less than 1.0 N/mm².

The aforementioned preparations [5] to [7] are also encompassed in the“preparation (C)”.

Here, whether or not the “ratio of the medicament in an unchanged formand a metabolite of the medicament after transfer into blood is higherthan that by oral administration” is evaluated as follows.

Each preparation is administered orally or oral-mucosally, the plasmaconcentration of both the unchanged form and metabolite after lapse ofeach time period is measured, and the area under the plasmaconcentration time curve (AUC) of the both is calculated according tothe trapezoidal rule. The ratio of the unchanged form and metabolite(i.e., AUC of unchanged form/AUC of metabolite) in each preparation iscalculated.

In this case, when the ratio by oral-mucosal administration is higherthan that by oral administration, it is evaluated “the ratio of amedicament in an unchanged form and a metabolite of the medicament aftertransfer into blood is higher than that by oral administration”.

As for the specific preparations to be subjected to a test and testmethods, the below-mentioned Experimental Example 4 can be referred to.However, when a substantially similar evaluation is possible, the methodis not limited to that of Experimental Example 4.

While the dosage forms of preparation (A), preparation (B) andpreparation (C) are not particularly limited as long as they can beadministered from the oral mucosa. For example, tablet (e.g., sublingualtablet, buccal tablet), film, troche, solution, suspension, freeze-driedpreparation, chewing gum, spray and the like can be mentioned. Amongthese, tablet is preferable.

As the kind and amount of “compound A”, “masking agent”, “sugar”, “sugaralcohol” and “disintegrant” to be used for preparation (A), preparation(B) or preparation (C), those exemplified for the above-mentionedrapidly disintegrating preparation can be mentioned.

In the present specification, the absolute hardness is hardness per unitarea, and is defined according to the following formula.

absolute hardness (N/mm²)=hardness (N)/(thickness (mm)×diameter (mm))

In the present invention, the tablet hardness can be measured by atablet hardness tester (TH-303MP, Toyama Sangyo CO., LTD.).

In the present specification, the disintegration time is a valuemeasured by a disintegration tester (ODT-101, Toyama Sangyo CO., LTD.)for orally rapidly disintegrating tablet.

Preparations (A)-(C) can be produced, for example, according to theproduction method explained for “the rapidly disintegrating preparationof the present invention”. Particularly, when the dosage form ofpreparations (A)-(C) is tablet, such production method is preferable. Itis also possible to apply other techniques for orally disintegratingpreparations.

When the dosage form of preparations (A)-(C) is film, the preparationscan be produced according to a conventional method as follows. Forexample, the preparation can be produced by applying or spraying acoating solution (solution or suspension, solvent is, for example,purified water) containing a medicament, a film carrier, other filmcarriers used as necessary and the like to the surface of a supportmedium, and drying same (JP-B-3460538).

When the dosage form of preparations (A)-(C) is freeze-driedpreparation, the preparation can be produced according to a conventionalmethod as follows. For example, the preparation can be produced bymixing a medicament, a polymer, sugars and the like, and dissolving andlyophilizing them (Manufacturing Chemist, February 36 (1990)).

When the dosage form of preparations (A)-(C) is chewing gum, thepreparation can be produced according to a conventional method asfollows. For example, the preparation can be produced by adding amedicament, additive such as sweetener, flavor, colorant, softeningagent, flavoring substance and the like to a gum base containing a resinfor a gum base as a main component, wax, an emulsifier and a filler,uniformly kneading them in a kneader, and processing them into a plateform, a block form and the like (JP-A-2009-136240).

When the dosage form of preparations (A)-(C) is troche, the preparationcan be produced according to a general production method of tablets.

When the dosage form of preparations (A)-(C) is solution or suspension,the preparation can be produced according to a. general productionmethod of liquids.

When the dosage form of preparations (A)-(C) is spray, the preparationcan be produced according to a general production method of spray.

The preparation of the present invention can be safely administered to amammal (e.g., human, mouse, rat, rabbit, dog, cat, bovine, horse, swine,monkey), particularly human.

The dose of the preparation of the present invention varies depending onthe subject of administration, administration route, disease and thelike. For example, when a preparation for oral-mucosal absorptioncontaining compound A as a medicament is administered to an adult, thedose of compound A is about 0.0002—about 0.02 mg/kg body weight,preferably about 0.0002—about 0.01 mg/kg body weight, more preferablyabout 0.0002—about 0.005 mg/kg body weight, most preferably about0.0002—about 0.004 mg/kg body weight, which can be administered in oneto several portions a day.

It is known that melatonin secretion decreases to cause disorders in thecircadian rhythm in patients with bipolar disorders. Compound A is asuperior melatonin receptor agonist; and considered to be effective forthe prophylaxis or treatment of diseases possibly influenced bymelatonin. In fact, compound A is suggested to be effective for thetreatment of bipolar disorders (particularly maintenance of remissionphase) in the clinical evaluation by oral administration.

As mentioned above, the present invention provides a preparation showingsuperior absorption of compound A from the oral mucosa and improvedbioavailability thereof. Hence, a more effective method for theprophylaxis and/or treatment of bipolar disorders, and a more effectivedrug for the prophylaxis and/or treatment of bipolar disorders areprovided.

To be precise, by oral-mucosal administration of compound A to patientsaffected with bipolar disorders, the bipolar disorders can be preventedand/or treated. Specifically, such prophylaxis and/or treatment can beperformed by appropriately administering the preparation of the presentinvention to humans.

Here, the administration route of compound A is preferably sublingualadministration or buccal administration, and sublingual administrationis particularly preferable.

While the dose of compound A is as mentioned above, for administrationas a sublingual tablet or a buccal tablet, for example, a tabletcontaining 0.05-1.5 mg (preferably, 0.05-1.0 mg, more preferably,0.1-1.0 mg, and most preferably, 0.1 mg, 0.4 mg and 0.8 mg) of compoundA per tablet is preferably administered to patients in one to threeportions (preferably once) per day.

As the target disease, it is particularly effective for bipolar disorderI. Specifically, it is effective for the “treatment of depressionsymptoms (particularly, acute depression symptoms) associated withbipolar disorder” and “maintenance of remission phase of bipolardisorder”.

For the “prophylaxis and/or treatment of bipolar disorders byoral-mucosal administration of compound A”, other medicaments for theprophylaxis and/or treatment of bipolar disorders may be used incombination. Such other medicaments for the prophylaxis and/or treatmentof bipolar disorders to be used in combination with “compound A”(hereinafter referred to as “combination medicament”) may include moodstabilizer (e.g. lithium, valproic acid, carbamazepine, lamotrigine,etc) and antipsychotics (e.g. quetiapine, olanzapine, etc), and acombination of one or more medicaments selected from them. In additionthereto, one or more SSRI (selective serotonin reuptake inhibitors)(e.g. fluvoxamine, paroxetine, escitalopram, fluoxetine, citalopram,etc) may also be administered in combination with “compound A” and theaforementioned “combination medicament”.

The administration mode of the “combination medicament” is notparticularly restricted, and it is sufficient that “compound A” and“combination medicament” be combined in administration. Examples of suchadministration mode include the following:

-   (1) administration of a single preparation obtained by    simultaneously processing “compound A” and “combination medicament”,-   (2) simultaneous administration of two kinds of preparations of    “compound A” and “combination medicament”, which have been    separately produced, by the same administration route,-   (3) administration of two kinds of preparations of “compound A” and    “combination medicament”, which have been separately produced, by    the same administration route in a staggered manner,-   (4) simultaneous administration of two kinds of preparations of    “compound A” and “combination medicament”, which have been    separately produced, by different administration routes,-   (5) administration of two kinds of preparations of “compound A” and    “combination medicament”, which have been separately produced, by    different administration routes in a staggered manner (e.g.,    administration in the order of “compound A” and “combination    medicament”, or in the reverse order) and the like.

The dosage of the “combination medicament” may be determined accordingto the dose clinically used, and can be appropriately selected dependingon an administration subject, administration route, seriousness of thedisease, combination, and the like.

The “combination medicament” can be administered in the same dosage formas clinically used or in a different dosage form suitable for thiscombination therapy.

When compound A is administered oral-mucosally to a human subject, theblood kinetic of it is quite similar to that of the endogenousmelatonin, and therefore compound A can regulate circadian rhythm, whichis thought to be disturbed in bipolar patients, better than existingdrugs and even melatonin/other melatonin agonists. Thus, compound A isexpected to show superior effect on bipolar disease to existing drugs.In addition, this circadian rhythm regulating effect can also translateinto better normalizing circadian rhythm and/or sleep/awake cycle inbipolar patients.

EXAMPLES

The present invention is explained in more detail in the following byreferring to Examples, which are not to be construed as limitative. Thepreparation additives (e.g., D-mannitol, microcrystalline cellulose, andthe like) used in the following Examples and Comparative Examples werethe Japanese Pharmacopoeia 15th Edition or Japanese PharmaceuticalExcipients 2003 compatible products.

Example 1

-   (1) D-Mannitol (PEARLITOL 50C, Roquette) (450.0 g) was dissolved in    purified water (2550 g) to give a coating solution. Compound A    (150.5 g), D-mannitol (3068 g), microcrystalline cellulose (CEOLUS    PH-101, Asahi Kasei Corporation) (112.5 g), and partly    pregelatinized starch (PCS, Asahi Kasei Corporation) (450.0 g) were    uniformly mixed in a fluid bed dryer granulator (FD-5S, POWREX    CORPORATION), granulated while spraying the coating solution (3000    g), and dried to give a granulated powder. A part of the obtained    granulated powder was ground in a power mill grinding machine (P-3,    SHOWA KAGAKU KIKAI CO., LTD.) using a 1.5 mmφ punching screen to    give a sieved powder.-   (2) To the obtained sieved powder (1692 g) were added crospovidone    (Kollidon CL-F, BASF) (90 g) and sodium stearyl fumarate (PRUV, JRS    PHARMA) (18 g), and the mixture was mixed in a tumbler mixer (TM-30,    SHOWA KAGAKU KIKAI CO., LTD.) to give a mixed powder.-   (3) The mixed powder was tableted by a rotary tableting machine    (AQUA 08242L2JI, Kikusui Seisakusho Ltd.) using a 4 mmφ punch    (tableting pressure: 4 kN, weight per tablet: 30 mg) to give a    tablet.

Composition of Preparation (30 mg)

compound A 1.0 mg D-mannitol (in granules) 20.45 mg  D-mannitol (incoating layer) 3.0 mg microcrystalline cellulose 0.75 mg  partlypregelatinized starch 3.0 mg crospovidone 1.5 mg sodium stearyl fumarate0.3 mg total  30 mg

Comparative Example 1

Polyethylene glycol 400 (PEG400) (Wako Pure Chemical Industries, Ltd.)(15 g) was dissolved in purified water (35 g) to give PEG400 solution.Compound A (12.5 mg) was added to PEG400 solution (50 ml), and themixture was stirred and insonated, and filtered using a hydrophilicfilter (0.45 μm). The obtained compound A solution was divided intosmall portions (1 ml each).

Composition of Preparation (1 ml)

compound A  0.25 mg PEG400 300.0 mg purified water 700.0 mg total1000.25 mg 

Comparative Example 2

-   (1) Hydroxypropylcellulose (HPC-L, NIPPON SODA CO., LTD.) (40 g) was    dissolved in purified water (627 g) to give a binding solution.    Compound A (2.5 g), lactose (DMV INTERNATIONAL) (1053.5 g), and corn    starch (Japan Corn Starch Co., Ltd.) (160 g) were uniformly mixed in    a fluid bed dryer granulator (MP-01, POWREX CORPORATION), granulated    while spraying the binding solution (667 g), and dried to give a    granulated powder. The obtained granules were sieved through a 16    mesh (aperture 1.0 mm) sieve to give a sieved powder.-   (2) Corn starch (17 g) and magnesium stearate (5 g) were added to    the obtained sieved powder (628 g) and mixed in a bag to give a    mixed powder.-   (3) The mixed powder was tableted by a rotary tableting machine    (compact tableting machine, Kikusui Seisakusho Ltd.) by using a 4    mmφ punch (tableting pressure: 7 kN, weight per tablet: 130 mg) to    give a tablet (core tablet).-   (4) Hydroxypropylmethylcellulose (TC-5R) (22.44 g) and Copovidone    (4.5 g) were dissolved in purified water (198 g) and dispersed    therein to give dispersion I. Titanium oxide (25 g) and yellow    ferric oxide (0.5 g) were dispersed in purified water (450 g) to    give dispersion II. Dispersion II was added to dispersion I, and the    mixture was stirred to give a coating solution. The coating solution    was sprayed on the core tablet obtained in (3) until the weight of    the core tablet increased by 5 mg per tablet by using a coater (High    Coater HC-LABO, Freund Corporation) to give a film-coated tablet    having the following composition.

Composition of Preparation (135 mg)

compound A 0.25 mg lactose 105.35 mg corn starch 19.4 mghydroxypropylcellulose 4.0 mg magnesium stearate 1.0 mghydroxypropylmethylcellulose 3.74 mg Copovidone 0.75 mg titanium oxide0.5 mg yellow ferric oxide 0.01 mg total 135 mg

Example 2

-   (1) D-Mannitol (PEARITOL 50C, Roquette) (120 g) was dissolved in    purified water (680 g) to give a coating solution. Compound A (10    g), D-mannitol (848 g), microcrystalline cellulose (CEOLUS PH-101,    Asahi Kasei Corporation) (30 g), and partly pregelatinized starch    (PCS, Asahi Kasei Corporation) (120 g) were uniformly mixed in a    fluid bed dryer granulator (MP-01, POWREX CORPORATION), granulated    while spraying a coating solution (800 g), and dried to give a    granulated powder. The obtained granules were sieved through a 16    mesh (aperture 1.0 mm) sieve to give a sieved powder.-   (2) The obtained sieved powder (28.2 g), crospovidone (Kollidon    CL-F, BASF) (1.5 g) and sodium stearyl fumarate (0.3 g) were mixed    in a glass bottle. The obtained mixture was tableted (tableting    pressure: 3 KN/punch, tablet weight per tablet: 30 mg) by an    AUTOGRAPH (AG-5000B, SHIMADZU Corporation) using a 4 mmφ punch to    give a core tablet with the following composition.

Composition of Preparation (30 mg)

compound A 0.25 mg D-mannitol (in granules) 21.2 mg D-mannitol (incoating layer) 3.0 mg microcrystalline cellulose 0.75 mg partlypregelatinized starch 3.0 mg crospovidone 1.5 mg sodium stearyl fumarate0.3 mg total 30 mg

Comparative Example 3

PEG400 (Wako Pure Chemical Industries, Ltd.) (60 g) was dissolved inpurified water (110 g) to give PEG400 solution. Compound A (100.0 mg)was added to the PEG400 solution (100 ml), and the mixture was stirredand insonated, and filtered using a hydrophilic filter (0.45 μm). Theobtained compound A solution was divided into small portions (1 mleach).

Composition of Preparation (1 ml)

compound A 1.0 mg PEG400 352.9 mg purified water 647.1 mg total 1001 mg

Comparative Example 4

-   (1) Hydroxypropylcellulose (HPC-L, NIPPON SODA CO., LTD.) (660 g)    was dissolved in purified water (10230 g) to give a binding    solution. Compound A (165.3 g), lactose (DMV INTERNATIONAL) (17260    g), and corn starch (Japan Corn Starch Co., Ltd.) (2640 g) were    uniformly mixed in a fluid bed dryer granulator (FD-S2, POWREX    CORPORATION), granulated while spraying a binding solution (10890    g), and dried to give a granulated powder. This granulation step was    performed twice. A part of the obtained granulated powder was ground    by a power mill grinding machine (P-3, SHOWA KAGAKU KIKAI CO., LTD.)    using a 1.5 mmφ punching screen to give a sieved powder.-   (2) Corn starch (1013 g) and magnesium stearate (298 g) were added    to the obtained sieved powder (37430 g), and the mixture was mixed    in a tumbler mixer (TM20-0-0, Suehiro Kakoki Co., Ltd.) to give a    mixed powder.-   (3) The mixed powder was tableted by a rotary tableting machine    (AQUARIUS 36K, Kikusui Seisakusho Ltd.) by using a 7 mmφ punch    (tableting pressure: 7 kN, weight per tablet: 130 mg) to give a    tablet (core tablet).-   (4) Hydroxypropylmethylcellulose (TC-5R, Shin-Etsu Chemical Co.,    Ltd.) (1548 g) and Copovidone (310.5 g) were dissolved in purified    water (16150 g) and dispersed therein to give dispersion I. Titanium    oxide (207 g) and yellow ferric oxide (4.14 g) were dispersed in    purified water (1822 g) to give dispersion II. Dispersion II was    added to dispersion I, and the mixture was stirred to give a coating    solution. Using a coater (High Coater HCF-100N, Freund Corporation),    the coating solution was sprayed on the core tablet obtained in (3)    until the weight of the core tablet increased by 5 mg per tablet to    give a film-coated tablet having the following composition.

Composition of Preparation (135 mg)

compound A 1.0 mg lactose 104.6 mg corn starch 19.4 mghydroxypropylcellulose 4.0 mg magnesium stearate 1.0 mghydroxypropylmethylcellulose 3.74 mg Copovidone 0.75 mg titanium oxide0.5 mg yellow ferric oxide 0.01 mg total 135 mg

Example 3

-   (1) D-mannitol (PEARLITOL 50C, Roquette) (120 g) was dissolved in    purified water (680 g) to give a coating solution. Compound A (40    g), D-mannitol (818 g), microcrystalline cellulose (CEOLUS PH-101,    Asahi Kasei Corporation) (30 g), and partly pregelatinized starch    (PCS, Asahi Kasei Corporation) (120 g) were uniformly mixed in a    fluid bed dryer granulator (MP-01, POWREX CORPORATION), granulated    while spraying the coating solution (800 g), and dried to give a    granulated powder. The obtained granules were sieved through a 16    mesh (aperture 1.0 mm) sieve to give a sieved powder.-   (2) The obtained sieved powder (28.2 g), crospovidone (Kollidon    CL-F, BASF) (1.5 g) and sodium stearyl fumarate (0.3 g) were mixed    in a glass bottle. The obtained mixture was tableted (tableting    pressure: 3 KN/punch, tablet weight per tablet: 30 mg) by an    AUTOGRAPH (AG-5000B, SHIMADZU Corporation) by using a 4 mmφ punch to    give a core tablet with the following composition.

Composition of Preparation (30 mg)

compound A 1.0 mg D-mannitol (in granules) 20.45 mg D-mannitol (incoating, layer) 3.0 mg microcrystalline cellulose 0.75 mg partlypregelatinized starch 3.0 mg crospovidone 1.5 mg sodium stearyl fumarate0.3 mg total 30 mg

Example 4

Compound A (5 g) and CMEC (20 g) were dissolved in acetone:ethanol=3:2mixed solution (500 ml), and spray-dried by a spray dryer (Pulvis MiniSpray, YAMATO SCIENTIFIC CO., LTD.). The obtained solid dispersionpowder was dried in vacuo at 40° C. for 16 hr. To the solid dispersionpowder (0.5 g) was added D-mannitol (PEARLITOL 100SD, Roquette) (11.5 g)and mixed in a bottle. The obtained mixed powder was divided into smallportions (120 mg each).

Composition of Preparation (120 mg)

compound A 1.0 mg CMEC 4.0 mg D-mannitol 115.0 mg total 120 mg

Example 5

Hydroxypropyl-β-cyclodextrin (hereinafter sometimes referred to asHP-β-CyD) (KLEPTOSE HPB, Roquette) (75 g) was dissolved in purifiedwater (422.5 g). Compound A (2.5 g) was dissolved in the obtainedHP-β-CyD aqueous solution to give a coating solution. D-Mannitol(PEARLITOL 50C, Roquette) (200 g) and microcrystalline cellulose (CEOLUSPH-101, Asahi Kasei Corporation) (7.5 g) were uniformly mixed in a fluidbed dryer granulator (MP-01, POWREX CORPORATION), granulated whilespraying the coating solution (500 g), and dried to give a granulatedpowder. The obtained granules were sieved through a 16 mesh (aperture1.0 mm) sieve to give a sieved powder. The obtained sieved powder wasdivided into small portions (114 mg each).

Composition of Preparation (114 mg)

compound A 1.0 mg HP-β-CyD 30.0 mg D-mannitol 80.0 mg microcrystallinecellulose 3.0 mg total 114 mg

Example 6

-   (1) D-Mannitol (PEARLITOL 50C, Roquette) (450 g) was dissolved in    purified water (2550 g) to give a coating solution. Compound A (37.6    g), D-mannitol (3180 g), microcrystalline cellulose (CEOLUS PH-101,    Asahi Kasei Corporation) (112.5 g), and partly pregelatinized starch    (PCS, Asahi Kasei Corporation) (450 g) were uniformly mixed in a    fluid bed dryer granulator (FD-5S, POWREX CORPORATION), granulated    while spraying the coating solution (3000 g), and dried to give a    granulated powder. A part of the obtained granulated powder was    ground by a power mill grinding machine (P-3, SHOWA KAGAKU KIKAI    CO., LTD.) using a 1.5 mmφ punching screen to give a sieved powder.-   (2) Crospovidone (Kollidon CL-F, BASF) (90 g) and sodium stearyl    fumarate (18 g) were added to the obtained sieved powder (1692 g),    and the mixture was mixed in a tumbler mixer (TM-15S, SHOWA KAGAKU    KIKAI CO., LTD.) to give a mixed powder.-   (3) The mixed powder was tableted by a rotary tableting machine    (AQUARIUS 2L, Kikusui Seisakusho Ltd.) by using a 4 mmφ punch    (tableting pressure: 4 kN, weight per tablet: 30 mg) to give a core    tablet with the following composition.

Composition of Preparation (30 mg)

compound A 0.25 mg D-mannitol (in granules) 21.2 mg D-mannitol (incoating layer) 3.0 mg microcrystalline cellulose 0.75 mg partlypregelatinized starch 3.0 mg crospovidone 1.5 mg sodium stearyl fumarate0.3 mg total 30 mg

Example 7

-   (1) D-mannitol (PEARLITOL 50C, Roquette) (450 g) was dissolved in    purified water (2550 g) to give a coating solution. Compound A    (150.5 g), D-mannitol (3068 g), microcrystalline cellulose (CEOLUS    PH-101, Asahi Kasei Corporation) (112.5 g), and partly    pregelatinized starch (PCS, Asahi Kasei Corporation) (450 g) were    uniformly mixed in a fluid bed dryer granulator (FD-5S, POWREX    CORPORATION), granulated while spraying the coating solution (3000    g), and dried to give a granulated powder. A part of the obtained    granulated powder was ground by a power mill grinding machine (P-3,    SHOWA KAGAKU KIKAI CO., LTD.) using a 1.5 mmφ punching screen to    give a sieved powder.-   (2) Crospovidone (Kollidon CL-F, BASF) (90 g) and sodium stearyl    fumarate (18 g) were added to the obtained sieved powder (1692 g),    and the mixture was mixed in a tumbler mixer (TM-15S, SHOWA KAGAKU    KIKAI CO., LTD.) to give a mixed powder.-   (3) The mixed powder was tableted by a rotary tableting machine    (AQUARIUS 2L, Kikusui Seisakusho Ltd.) by using a 4 mmφ punch    (tableting pressure: 4 kN, weight per tablet: 30 mg) to give a core    tablet with the following composition.

Composition of Preparation (30 mg)

compound A 1.0 mg D-mannitol (in granules) 20.45 mg D-mannitol (incoating layer) 3.0 mg microcrystalline cellulose 0.75 mg partlypregelatinized starch 3.0 mg crospovidone 1.5 mg sodium stearyl fumarate0.3 mg total 30 mg

Comparative Example 5

-   (1) Hydroxypropylcellulose (HPC-L, NIPPON SODA CO., LTD.) (660 g)    was dissolved in purified water (10230 g) to give a binding    solution. Compound A (1320 g), lactose (DMV INTERNATIONAL) (16104    g), and corn starch (Japan Corn Starch Co., Ltd.) (2640 g) were    uniformly mixed in a fluid bed dryer granulator (FD-S2, POWREX    CORPORATION), granulated while spraying the binding solution (10890    g), and dried to give a granulated powder. This granulation step was    performed twice. A part of the obtained granulated powder was ground    by a power mill grinding machine (P-3, SHOWA KAGAKU KIKAI CO., LTD.)    using a 1.5 mmφ punching screen to give a sieved powder.-   (2) Corn starch (1013 g) and magnesium stearate (298 g) were added    to the obtained sieved powder (37430 g), and the mixture was mixed    in a tumbler mixer (TM20-0-0, Suehiro Kakoki Co., Ltd.) to give a    mixed powder.-   (3) The mixed powder was tableted by a rotary tableting machine    (AQUARIUS 36K, Kikusui Seisakusho Ltd.) by using a 7 mmφ punch    (tableting pressure: 7 kN, weight per tablet: 130 mg) to give a    tablet (core tablet).-   (4) Hydroxypropylmethylcellulose (TC-5R, Shin-Etsu Chemical Co.,    Ltd.) (1548 g) and Copovidone (310.5 g) were dissolved and dispersed    in purified water (16150 g) to give dispersion I. Titanium oxide    (207 g) and yellow ferric oxide (4.14 g) were dispersed in purified    water (1822 g) to give dispersion II. Dispersion II was added to    dispersion I, and the mixture was stirred to give a coating    solution. Using a coater (High Coater HCF-100N, Freund Corporation),    the coating solution was sprayed on the core tablet obtained in (3)    until the weight of the core tablet increased by 5 mg per tablet to    give a film-coated tablet having the following composition.

Composition of Preparation (135 mg)

compound A 8.0 mg lactose 97.6 mg corn starch 19.4 mghydroxypropylcellulose 4.0 mg magnesium stearate 1.0 mghydroxypropylmethylcellulose 3.74 mg Copovidone 0.75 mg titanium oxide0.5 mg yellow ferric oxide 0.01 mg total 135 mg

Example 8

-   (1) D-Mannitol (PEARLITOL 50C, Roquette) (510 g) was dissolved in    purified water (2890 g) to give a coating solution. Compound A    (17.05 g), D-mannitol (3114 g), microcrystalline cellulose (CEOLUS    PH-101, Asahi Kasei Corporation) (127.5 g), and partly    pregelatinized starch (PCS, Asahi Kasei Corporation) (510 g) were    uniformly mixed in a fluid bed dryer granulator (FD-5S, POWREX    CORPORATION), granulated while spraying the coating solution (3400    g), and dried to give a granulated powder. A part of the obtained    granulated powder was sieved using a round sieve (mesh size 1.0 mmφ)    to give sieved powder A.-   (2) The same step as (1) was performed to give sieved powder B.-   (3) To the obtained sieved powder A (3146.5 g) and sieved powder B    (3146.5 g) were added crospovidone (Kollidon CL-F, BASF) (375.0 g),    aspartame (750 g), vanillin (7.5 g) and sodium stearyl fumarate (75    g), and the mixture was mixed in a tumbler mixer (TM-60S, SHOWA    KAGAKU KIKAI CO., LTD.) to give a mixed powder.-   (4) The mixed powder was tableted by a rotary tableting machine    (AQUARIUS 2L, Kikusui Seisakusho Ltd.) using a 4 mmφ punch    (tableting pressure: 4 kN, weight per tablet: 30 mg) to give a core    tablet with the following composition.

Composition of Preparation (30 mg)

compound A 0.1 mg D-mannitol (in granules) 18.32 mg D-mannitol (incoating layer) 3.0 mg microcrystalline cellulose 0.75 mg partlypregelatinized starch 3.0 mg crospovidone 1.5 mg sodium stearyl fumarate0.3 mg aspartame 3.0 mg vanillin 0.03 mg total 30 mg

Example 9

-   (1) D-Mannitol (PEARLITOL 50C, Roquette) (510 g) was dissolved in    purified water (2890 g) to give a coating solution. Compound A    (68.20 g), D-mannitol (3063 g), microcrystalline cellulose (CEOLUS    PH-101, Asahi Kasei Corporation) (127.5 g), and partly    pregelatinized starch (PCS, Asahi Kasei Corporation) (510 g) were    uniformly mixed in a fluid bed dryer granulator (FD-5S, POWREX    CORPORATION), granulated while spraying the coating solution (3400    g), and dried to give a granulated powder. A part of the obtained    granulated powder was sieved by using a round sieve (mesh size 1.0    mmφ) to give sieved powder A.-   (2) The same step as (1) was performed to give sieved powder B.-   (3) To the obtained sieved powder A (3146.5 g) and sieved powder B    (3146.5 g) were added crospovidone (Kollidon CL-F, BASF) (375.0 g),    aspartame (750 g), vanillin (7.5 g) and sodium stearyl fumarate (75    g), and the mixture was mixed in a tumbler mixer (TM-60S, SHOWA    KAGAKU KIKAI CO., LTD.) to give a mixed powder.-   (4) The mixed powder was tableted by a rotary tableting machine    (AQUARIUS 2L, Kikusui Seisakusho Ltd.) using a 4 mmφ punch    (tableting pressure: 4 kN, weight per tablet: 30 mg) to give a core    tablet with the following composition.

Composition of Preparation (30 mg)

compound A 0.4 mg D-mannitol (in granules) 18.02 mg D-mannitol (incoating layer) 3.0 mg microcrystalline cellulose 0.75 mg partlypregelatinized starch 3.0 mg crospovidone 1.5 mg sodium stearyl fumarate0.3 mg aspartame 3.0 mg vanillin 0.03 mg total 30 mg

Example 10

-   (1) D-Mannitol (PEARLITOL 50C, Roquette) (510 g) was dissolved in    purified water (2890 g) to give a coating solution. Compound A    (136.4 g), D-mannitol (2995 g), microcrystalline cellulose (CEOLUS    PH-101, Asahi Kasei Corporation) (127.5 g), and partly    pregelatinized starch (PCS, Asahi Kasei Corporation) (510 g) were    uniformly mixed in a fluid bed dryer granulator (FD-5S, POWREX    CORPORATION), granulated while spraying the coating solution (3400    g), and dried to give a granulated powder. A part of the obtained    granulated powder was sieved by using a round sieve (mesh size 1.0    mmφ) to give sieved powder A.-   (2) The same step as (1) was performed to give sieved powder B.-   (3) To the obtained sieved powder A (3146.5 g) and sieved powder B    (3146.5 g) were added crospovidone (Kollidon CL-F, BASF) (375.0 g),    aspartame (750 g), vanillin (7.5 g) and sodium stearyl fumarate (75    g), and the mixture was mixed in a tumbler mixer (TM-60S, SHOWA    KAGAKU KIKAI CO., LTD.) to give a mixed powder.-   (4) The mixed powder was tableted by a rotary tableting machine    (AQUARIUS 2L, Kikusui Seisakusho Ltd.) using a 4 mmφ punch    (tableting pressure: 4 kN, weight per tablet: 30 mg) to give a core    tablet with the following composition.

Composition of Preparation (30 mg)

compound A 0.8 mg D-mannitol (in granules) 17.62 mg D-mannitol (incoating layer) 3.0 mg microcrystalline cellulose 0.75 mg partlypregelatinized starch 3.0 mg crospovidone 1.5 mg sodium stearyl fumarate0.3 mg aspartame 3.0 mg vanillin 0.03 mg total 30 mg

Experimental Example 1

The tablet obtained in Example 1 was measured for the tablet hardnessand disintegration time. The tablet hardness was measured by a tablethardness tester (TH-303MP, Toyama Sangyo CO., LTD.) (n=10). Thedisintegration time was measured by a disintegration tester (ODT-101,Toyama Sangyo CO., LTD.) (n=6). The results are shown in Table 1.

Disintegration Tester Conditions

-   rotation number: 50 rpm-   plummet: 15 mmφ, (10 g)

TABLE 1 hardness 21N absolute hardness 2.73 N/mm² disintegration 5.24sec

Experimental Example 2

The mixed powder obtained in Example 1 was measured for the dissolutionproperty. The mixed powder (15 g) (corresponding to 500 mg of compoundA) was placed in the Japanese Pharmacopoeia 2nd fluid (500 ml), and thedissolution property was evaluated by the Paddle Method, rotation number25 rpm, 37° C. After adding the sample, the eluate was sampled with time(0.25 min, 0.5 min, 0.75 min, 1 min, 5 min, 15 min, 30 min), filtered byusing a hydrophilic filter (0.45 μm), dissolved by 10-fold diluting withthe extract (water/acetonitrile mixed solution (1:1)), and quantified byhigh performance liquid column chromatography (HPLC) under the followingconditions to calculate the solubility. The results are shown in Table2.

HPLC Conditions

-   detector: ultraviolet ray absorption spectrophotometer-   measurement wavelength: 240 nm-   column: YMC-Pack ODS-AM AM-307, 5 μm, inner diameter: 4.6 mm length:    75 mm-   column temperature: 25° C.-   mobile phase: 0.01 mol/L phosphate buffer/acetonitrile mixed    solution (5:3)-   flow: 1.2 ml/min

TABLE 2 time (min) compound A concentration (mg/ml) 0 0 0.25 0.103 0.50.218 0.75 0.225 1 0.237 5 0.273 15 0.279 30 0.280

Experimental Example 3

The injections obtained in Comparative Examples 1, 3, oral tabletsobtained in Comparative Examples 2, 4 and preparations for oral-mucosalabsorption obtained in Examples 2-5 were measured for blood kineticsafter intravenous injection, oral, sublingual and buccal administrationsin Macaca fascicularis under fasting conditions. The plasmaconcentration before administration, and 5 min, 10 min, 20 min, 30 min,60 min, 120 min, 240 min and 360 min after administration was measured,and the area under the plasma concentration time curve (AUC) wascalculated according to the trapezoidal rule. In addition,bioavailability (BA) was determined by calculating the ratio of AUC byoral, sublingual or buccal administration to AUC by intravenousinjection. The results are shown in Table 3.

TABLE 3 administration dose (mg) route preparation T_(max) (min) C_(max)(ng/ml) AUC (ng · min/ml) BA (%) 0.25 intravenous Comparative 9.0 ± 6.563.4 ± 14.1 2933.8 ± 578.5 — injection Example 1 oral Comparative 132.0± 130.1 0.4 ± 0.1  54.4 ± 22.6 1.9 Example 2 sublingual Example 2 34.0 ±15.2 12.5 ± 5.9  1218.0 ± 655.8 41.5 buccal Example 6 36.0 ± 18.0 22.7 ±12.3 1656.0 ± 726.0 56.4 1 intravenous Comparative 3.2 ± 1.6 509.7 ±248.9 16889.5 ± 2057.2 — injection Example 3 oral Comparative  8.0 ±13.0 0.8 ± 1.2  21.3 ± 35.8 0.1 Example 4 sublingual Example 3 28.0 ±4.5  38.5 ± 12.8  3062.4 ± 1129.9 18.1 Example 4 42.0 ± 16.0 31.4 ± 8.6 3206.9 ± 809.9 19.0 Example 5 48.0 ± 16.0 46.6 ± 13.8  4568.4 ± 1286.327.0 buccal Example 7 36.0 ± 12.0 87.1 ± 21.2  5862.0 ± 1038.0 34.7

Experimental Example 4

Oral preparation and preparation for oral-mucosal absorption weremeasured for blood kinetics of unchanged form and activity metaboliteM-II after oral or sublingual administration to human. The plasmaconcentration before administration, and 5 min, 10 min, 15 min, 20 min,30 min, 45 min, 60 min, 90 min, 120 min, 180 min, 240 min, 360 min, 480min, 600 min, 720 min and 1440 min after administration was measured,and the area under the plasma concentration time curve (AUC) wascalculated according to the trapezoidal rule. The results are shown inTable 4.

TABLE 4 measurement dose administration T_(max) C_(max) AUC (0-tlqc) AUC(0-inf) substance (mg) route preparation (min) (ng/ml) (ng · min/ml) (ng· min/ml) unchanged 8 oral Comparative 45.0 4.76 ± 5.19 364.8 ± 383.0334.2 ± 347.6 form Example 8 (19.8-120.0) 0.5 sublingual Example 6 15.04.74 ± 1.52 215.4 ± 64.6  223.8 ± 67.1  (9.0-30.0) active 8 oralComparative 60.0 68.1 ± 23.2 12495.0 ± 4998.0  12747.0 ± 5098.8 metabolite Example 8 (30.0-180.0) M-II 0.5 sublingual Example 6 45.04.18 ± 1.26 596.4 ± 280.3 730.8 ± 285.0 (15.0-60.0) 

Example 10

A methylcellulose powder (0.5 g) was dissolved in water (99.5 g) underice-cooling, and compound A (100 mg) was added to the obtained solution(10 ml), stirred and uniformly dispersed therein. The obtainedsuspension was filled in a spray device (spray amount: 100 μL/time) togive an oral spray preparation.

Example 11

Hydroxypropyl-β-cyclodextrin (HP-β-CyD) (40 g) was dissolved in water(60 g), and compound A (100 mg) was added to the obtained solution (10ml), stirred and dissolved therein. The obtained solution was filled ina spray device (spray amount: 100 μL/time) to give an oral spraypreparation.

Example 12

Compound A (100 mg), polyvinylpyrrolidone (1 g) andhydroxypropylcellulose (18 g) were added to ethanol (100 ml) anddissolved by stirring. The obtained solution (1 ml) was spread flat on aplastic sheet and dried to give an orally rapidly dissolving filmpreparation.

Example 13

Compound A (100 mg), D-mannitol (5 g) and hydroxypropylcellulose (100mg) were added to a mixed solution (100 ml) of water and ethanol (4:1)and dissolved by stirring. The obtained solution (1 ml) was dispensed toa pocket of a blister pack with vinyl chloride resin as an inner film,frozen at −30° C., and dried by a vacuum dryer to give an orally rapidlydissolving freeze-dried preparation.

INDUSTRIAL APPLICABILITY

The present invention can provide a novel preparation showing improvedbioavailability of a medicament and a production method thereof and thelike.

When compound A is administered nasally (through nasal mucosa) to ahuman subject, it is expected to be effective on prophylaxis and/ortreatment of bipolar disease as administered oral-mucosally as disclosedabove. Compound A can be administered, for example, in the form of theformulation as disclosed in WO 01/15735.

When compound A is administerd to a human subject, it can be alsoadministered in the dosage forms suitable for inhalation (e.g.nebulizer, etc) in order to prevent and/or treat bipolar disease. Thedosage forms can be produced according to a general production method inthis art. The dose of compound A can be decided referring to, forexample, the preparations (A) to (C) in the present application.

This application is based on patent application Nos. 2011-007371 and2011-227333 filed in Japan, the contents of which are incorporated infull herein.

1-8. (canceled)
 9. A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideas a medicament; wherein the preparation comprises at least oneadditional feature selected from the group consisting of (i) a higherratio of the medicament in an unchanged form and a metabolite of themedicament after transfer into blood than that by oral administration,(ii) a masking agent, wherein the preparation comprises not less thanabout 10-fold improved bioavailability of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,as compared to that by oral administration and (iii) a sugar or sugaralcohol and a disintegrant, wherein the preparation comprises not lessthan about 10-fold improved bioavailability of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,as compared to that by oral administration.
 10. The preparationaccording to claim 9, wherein the preparation further comprises adisintegration time of not more than 30 sec.
 11. The preparationaccording to claim 10, wherein the preparation further comprises anabsolute hardness of not less than 1.0 N/mm². 12.-16. (canceled)
 17. Thepreparation according to claim 9, which is a tablet.
 18. The preparationaccording to claim 9, which is in the form of a film, troche, solution,suspension, freeze-dried preparation, chewing gum or spray.
 19. A methodfor the prophylaxis and/or treatment of a bipolar disorder comprisingadministering(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideoral-mucosally to a human.
 20. The method according to claim 19, whereinthe oral-mucosal administration is sublingual administration or buccaladministration.
 21. The method according to claim 19, wherein(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideis administered in 0.05-1.0 mg per day.
 22. The method according toclaim 19, wherein the bipolar disorder is bipolar disorder I.
 23. Themethod according to claim 19, wherein the prophylaxis and/or treatmentof a bipolar disorder is a treatment of a depression symptom associatedwith the bipolar disorder or maintenance of a remission phase of thebipolar disorder.
 24. A drug for the prophylaxis and/or treatment of abipolar disorder, which comprises, as an active ingredient,(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideto be oral-mucosally administered to a human.
 25. The drug according toclaim 24, wherein the oral-mucosal administration is sublingualadministration or buccal administration.
 26. The drug according to claim24, wherein(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideis administered in 0.05-1.0 mg per day.
 27. The drug according to claim24, wherein the bipolar disorder is bipolar disorder I.
 28. The drugaccording to claim 24, wherein the prophylaxis and/or treatment of abipolar disorder is a treatment of a depression symptom associated withthe bipolar disorder or maintenance of a remission phase of the bipolardisorder. 29-33. (canceled)